Autotaxin (ATX) was originally described as a secreted product that induces cancer cell motility, and is now known to work by cleaving the choline moiety from lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA). LPA is a pleiotropic lipid mediator and when produced extracellularly, binds to G protein coupled receptors on its target cells. LPA has a very short half-life, and current thinking is that regulated expression of ATX results in discrete tissue environments enriched in LPA in vivo. LPA is a potent pro-motility agent implicated in lymphocyte trafficking, but our understanding of the ATX/LPA axis in mucosal immunity is in its infancy. Although circumstantial evidence implicates LPA in the pathogenesis of asthma, we do not understand how LPA is generated or acts within the lung in the context of allergic inflammation. Here we report that conditional deletion of ATX in the airway strikingly attenuates allergic airway inflammation and Th2 immune responses induced by house dust mite (HDM). We found that epithelial ATX deletion attenuated not only acute HDM- induced inflammation, but also the development of long-lived HDM-specific CD4+ resident memory cells. Using a combination of genetic and pharmacologic approaches to target ATX, together with state-of-the-art analyses of lung lysolipid levels and memory T cells, we will conduct mechanistic research defining new pathways of relevance to mucosal immunology and asthma pathobiology. By combining studies using relevant mouse models with novel pharmacologic antagonists, we aim to conductive innovative and high-impact research with immediate translational potential. In Aim 1, we will determine how different cellular sources of ATX impact lung LPA levels, airway inflammation, and airway hyper-reactivity. In Aim 2, we will test the hypothesis that ATX-derived LPA promotes the retention of CD4+ T cells in the airway, resulting in the generation of long-lived resident memory cells. Aim 3 will use an innovative imaging platform to determine how the ATX/LPA axis impacts CD4+ interstitial motility. Taken together, our studies will deepen our understanding of fundamental pathways of mucosal immunity, and lay the foundation for future translational research in asthma.